syn‐Selective Epoxidation of Chiral Terminal Allylic Alcohols with a Titanium Salalen Catalyst and Hydrogen Peroxide

Abstract In the Sharpless asymmetric epoxidation of chiral secondary allylic alcohols, one substrate enantiomer is predominantly converted to the anti‐epoxy alcohol. We herein report the first highly syn‐selective epoxidation of terminal allylic alcohols using a titanium salalen complex as catalyst, at room temperature, and aqueous hydrogen peroxide as oxidant. With enantiopure terminal allylic alcohols as substrates, the epoxy alcohols were obtained with up to 98 % yield and up to >99 : 1 dr (syn). Catalyst loadings as low as 1 mol % can be applied without eroding the syn‐diastereoselectivity. Modification of the allylic alcohol to an ether does not affect the diastereoselectivity either [>99 : 1 dr (syn)]. Inverting the catalyst configuration leads to the anti‐product, albeit at lower dr (ca. 20 : 1). The synthetic potential is demonstrated by a short, gram‐scale preparation of a tetrahydrofuran building block with three stereocenters, involving two titanium salalen catalyzed epoxidation steps.


Instruments
Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker Avance I 300, a Bruker Avance 499, or a Bruker Avance III 500 instrument in CDCl3 at ambient temperature. Chemical shifts () are reported in ppm and are relative to the tetramethylsilane (TMS) signal ( 1 H) or solvent signals ( 13 C). Coupling constants were reported in Hz with the following abbreviations for multiplicities: br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet. Infrared (IR) spectra were recorded on a Shimadazu IRAffinity-1 spectrometer with ATR technique. Wave numbers were reported in cm -1 and the intensities of absorption bands are indicated by the following abbreviations: s = strong, m = medium, w = weak. GC-MS analysis was done on an Agilent Technologies 7890A instrument with injector and autosampler, and an Agilent Technologies 5975C Triple-Axis Detector. A HP-5 MS column (length: 30.0 m, inner diameter: 0.25 mm, film thickness: 0.25 µm) was used with H2 as carries gas and the following temperature program 50 °C, 5 min, 20 °C/min to 280 °C, 10 min. HR-GC-MS analysis was done on a Thermo Scientific Exactive GC with an Orbitrap Analyser. Chiral HPLC analysis was done on a HITACHI-Chromaster system with pump (5160), autosampler (5260), column oven (5310)

General procedure for the configurational assignment of the epoxy alcohols 4a-e
First, the racemic allylic alcohols rac-3a-e were subjected to epoxidation with mCPBA (see 2.2, "general procedure B"), affording mixtures of diastereomeric racemates. These racemic mixtures were assigned as syn and anti by 1 H NMR, according to Mihelich and Sharpless et al. [5] The NMR assignment of syn/anti to the major/minor racemates was then transferred to the GC-and HPLC-analyses. For the assignment of absolute configurations, the enantiomerically pure allylic alcohols 3a-e were epoxidized.

General preparative procedures
General procedure A: Enzymatic kinetic resolution of the allylic alcohols rac-3a-e The kinetic resolution was carried out according to the procedure of Porto et al.. [6] To a solution of the racemic allylic alcohol (3.77 mmol, 1.00 eq) in 30 mL n-hexane (HPLC grade), 120 mg of immobilized lipase was added. Vinyl acetate (37.8 mmol, 10.0 eq) was then added, and the reaction mixture was shaken at 150 rpm at room temperature in a stoppered 100 mL Erlenmeyer flask. The reaction was monitored via chiral GC. Upon complete consumption of one of the allylic alcohol substrates, the enzyme was filtered off and washed four times with 30 mL cyclohexane. The solvent was evaporated under reduced pressure, and the crude product was purified by flash column chromatography on silica.

General procedure B: Epoxidation of allylic alcohols with mCPBA
To a solution of the racemic allylic alcohol (1.78 mmol, 1.00 eq) in 20 mL dichloromethane was added mCPBA (ca. 75% peracid) (500 mg, ca. 2.20 mmol, ca. 1.25 eq). When the TLC control indicated full consumption of the allylic alcohol, the reaction was quenched with 20 mL sat. aq. Na2S2O3-solution or 20 mL sat. aq. Na2SO3-solution, and 20 mL sat. NaHCO3-solution. The phases were separated, and the aqueous phase was extracted three times with 15 mL dichloromethane. The combined organic phases were dried over MgSO4 or Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography on silica.

Preparation of enantiopure allylic alcohols
Kinetic resolution of racemic undec-1-en-3-ol (rac-3a) The kinetic resolution was performed on a 3.77 mmol scale according to general procedure A. The product (R)-undec-1-en-3-ol (3a) was obtained as a colorless liquid. Yield: 296 mg ( . Analytical data are in agreement with the literature. [7] The enantiomeric excess was determined to be 94% after hydrolysis of the acetate to the alcohol ent-3a by chiral GC (Lipodex A; see analytical details above).

Kinetic resolution of 1-phenylbut-3-en-2-ol (rac-3b)
The kinetic resolution was performed on a 1.09 mmol scale according to general procedure A.
The product (S)-4,4-dimethylpent-1-en-3-ol ( . Analytical data are in agreement with the literature. [10] The enantiomeric excess was determined to be 60% after hydrolysis of the acetate to the alcohol ent-3d by chiral GC (Chiralsil-DEX CB; see analytical details above).

Kinetic resolution of racemic α-vinylbenzyl alcohol (rac-3e)
The kinetic resolution was performed on a 11.2 mmol scale after general procedure A.

Preparation of (S)-(3-methoxyallyl)cyclohexane (6)
Under inert atmosphere, a solution of 140 mg (S)-1-cyclohexylprop-2-en-1-ol (3c, 1.00 mmol, 1.00 eq) in 2 mL THF was cooled to 0 °C. Sodium hydride [48 mg (60% in mineral oil), 2.00 mmol, 2.00 eq] was added, and the mixture was stirred at rt for 30 min. Methyl iodide (213 mg, 1.50 mmol, 1.50 eq) was then added, and the reaction mixture was stirred for 3 h. The reaction was quenched by addition of 10 mL sat. aq. NH4Cl-solution. The aqueous phase was extracted with dichloromethane (3x10 mL). The combined organic phases were washed with brine, dried over MgSO4, and filtered. The solvent was evaporated under reduced pressure, and the crude product was purified by flash column chromatography on silica gel (cHex:DCM = 7:3 to 100% DCM). The product was obtained as a colorless liquid. Yield: 140 mg.

Catalytic Epoxidations
General procedure for catalytic epoxidations A 5 mL reaction tube with a stirring bar (10 mm x 5 mm) was charged with the allylic alcohol (100 µmol, 1.00 eq), diphenyl ether (100 µmol, 1.00 eq, internal standard), 7.2 mg titanium salalen catalyst 2 (5 µmol, 0.05 eq) and 0.5 mL solvent. No inert atmosphere was applied. The solution was thermostated to 20 °C and stirred at 400 rpm. After 15 min, an aliquot (10 µL) was withdrawn with an Eppendorf pipette, passed through cotton/MgSO4:MnO2 (in a Pasteur pipette), and eluted with ethyl acetate. The epoxidation was then started by the addition of aqueous H2O2 (8.5 L, 150 µmol, 1.50 eq, 50 % w/w in water) with an Eppendorf pipette. Aliquots were withdrawn in regular intervals, treated like the t0-sample, and analyzed by chiral GC. For the NMR-characterization of the product epoxy alcohols 4a to 4e, the reaction mixtures were filtered through a small pad of MgSO4:MnO2. Solvents were removed from the filtrate under reduced pressure, and the residue was purified by flash column chromatography on silica.

Catalytic epoxidation of the enantiopure allylic alcohols 3a-e
According to the general procedure for catalytic epoxidations, reactions were performed on a 100 µmol scale, using the enantiopure allylic alcohols 3a-e as the substrate. Chloroform was used as solvent.

X-Ray crystal structure of (R,R)-cyclohexyl(oxiran-2-yl)methanol (4c)
Crystals suitable for X-ray crystallography were obtained by slow evaporation of a solution in n-pentane. Figure S1: Molecular structure (left) and ORTEP (right, four independent molecules in the unit cell) of the X-ray crystal structure of the epoxy alcohol 4c. Thermal ellipsoids are drawn at 50% probability level.

X-Ray crystal structure of (R,R)-1-(oxiran-2-yl)tridecan-1-ol (4f)
Crystals suitable for X-ray crystallography were obtained by slow evaporation of a solution in n-pentane.  Figure S2: Molecular structure (top) and ORTEP (bottom, two independent molecules in the unit cell) of the X-ray crystal structure of the epoxy alcohol 4f. Thermal ellipsoids are drawn at 50% probability level.